The long-term goal of the proposed research is to understand the mechanisms that mediate neuronal migration in mammals. In the vertebrate embryo, neurons frequently migrate long distances to reach their final positions, where they assemble into intricate networks responsible for complex functions such as learning and behavior. Many human neurological disorders result when neurons either migrate aberrantly or fail to migrate. Therefore, it is essential to understand the mechanisms mediating migration of specific neuronal types, so that the causes of and potential remedies for human brain disorders can eventually be identified. The proposed work employs the migration of facial branchiomotor neurons (FBMNs) in the zebrafish and mouse hindbrain as a model for neuronal migrations in mammals. Previous work demonstrated that a transmembrane protein Strabismus (Stbm) was necessary for FBMN migration in zebrafish. Stbm has been well studied for its role as a component of the wingless/Wnt signaling pathway in mediating polarized cellular behaviors and patterning events in an epithelial cell layer (planar cell polarity/PCP) in flies and vertebrates. However, we have accumulated compelling preliminary evidence that, during FBMN migration, Stbm may function independently of other components of the Wnt/PCP signaling pathway. It therefore appears that Stbm and Pricklel (Pk1), a cytoplasmic protein that potentially binds Stbm, use novel molecular and cellular mechanisms to regulate FBMN migration. In Aim 1, the roles of various domains within Stbm, and of two putative Stbm-interacting proteins, in FBMN migration in zebrafish will be studied using gain- and loss-offunction approaches. In Aim 2, the identity of the cell(s) in which Stbm and Pk1 functions are needed for FBMN migration will be determined using loss-of-function and cell transplantation methods. In Aim 3, the roles of Stbm and other PCP components in FBMN migration in mouse will be evaluated through detailed expression studies and analyses of mutant mice. Together, these experiments will generate novel insight into neuronal migration mechanisms in the vertebrate hindbrain.